The central hypothesis tested by this proposal is that extracellular ATP signaling is crucial for host surveillance function by human skin-resident T cells to protect from UV damage. This hypothesis will be tested by experiments: 1) Determining the functional role of eATP signaling on cytokines and effector molecules by skin- resident T cells and their capacity to induce repair and defense genes or apoptosis in keratinocytes; 2) examining whether CD39+ T regulatory cells and macrophages impair skin-resident T cell function in an ATP- dependent manner, and 3) elucidating the efficacy of purinergic receptor directed strategies to prevent and treat chronic skin inflammation. The proposed studies will expand our knowledge of how ATP regulates surveillance function in skin-resident T cells, evaluate new in vitro and in vivo models of skin inflammation, identify candidate purinergic receptors for drug targeting, and develop new tools for investigating and treating UV-induced skin inflammation and actinic keratoses to prevent tissue damage and malignant transformation. The research and career development components of this K08 award provide the necessary training for the applicant to become a successful independent investigator and to establish an independent research program.
Molecules released by stressed keratinocytes; such ATP; serve as danger associated molecules. This project investigates the functional roles of extracellular ATP and ATP-sensing receptors in controlling skin resident T cell function in UV-induced skin inflammation and premalignant actinic keratoses and focuses on the development of new models and treatments.
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